Somatosensory Integration and Masking of Complex Tactile Information: Peripheral and Cortical Contributions.

Nerve paresthesia is a sensory impairment experienced in clinical conditions such as diabetes. Paresthesia may "mask" or "compete" with meaningful tactile information in the patient's sensory environment. The two objectives of the present study were: (1) to determine if radiating paresthesia produces a peripheral mask, a central mask, or a combination; (2) to determine if a response competition experimental design reveals changes in somatosensory integration similar to a masking design. Experiment 1 assessed the degree of masking caused by induced radiating ulnar nerve paresthesia (a concurrent non-target stimulus) on a vibrotactile Morse code letter acquisition task using both behavioral and neurophysiological measures. Experiment 2 used a response competition design by moving the radiating paresthesia to the median nerve. This move shifted the concurrent non-target stimulus to a location spatially removed from the target stimuli. The task, behavioral and neurophysiological measures remained consistent. The induced paresthesia impacted letter acquisition differentially depending on the relative location of meaningful and non-meaningful stimulation. Paresthesia acted as a peripheral mask when presented to overlapping anatomical stimulation areas, and a central mask when presented at separate anatomical areas. These findings are discussed as they relate to masking, subcortical, and centripetal gating.

Using a Manipulation Check to Uncover Age-Related Difference in Focus of Attention Instruction During a Balance Task.

BACKGROUND/STUDY CONTEXT: A manipulation check was used to investigate whether there is an age-related difference in the adherence to specific external- and internal-focus instructional constraints. METHODS: Participants stood on a force platform and were to maintain a feedback cursor (representing their center of pressure) along the horizontal direction, within a target on a computer monitor. Trials were conducted with either an external focus of attention (keeping the feedback cursor within the target) or an internal focus of attention (keeping the weight evenly distributed between both legs). RESULTS: The finding showed that younger adults followed the experimental instructions; however, older adults relied on external visual information when they were asked to focus on the body movements. CONCLUSION: Age-related declines may contribute to attention allocation differences. The authors propose that specific manipulation checks be used to ensure proper adherence to instructions when comparing age-related differences in postural control.

On the Role of Error in Motor Learning.

The authors report 5 experiments that explored the role of error in motor learning. Participants practiced 4 distinct keypress sequences that varied in the amounts of advance information (i.e., choice) about which key to press next in the sequence. The amount of advance information resulted in differing levels of error during practice, which in general, was inversely related to retention performance. Although these findings support a beneficial role of error in motor learning, they also suggest that not all errors are equal in the learning process. Rather, we make a distinction between factors that induce errors that have desirable influences on learning compared to those that have undesirable effects.

Age-related changes in postural control to the demands of a precision task.

Optimal sensorimotor integration is needed to maintain the precision of a visuomotor postural task. Furthermore, cognitive resources have been suggested to be involved in maintaining balance, especially in older adults. This study investigated how older and younger adults differed in employing sensorimotor strategies in a dual-task situation. Older (age 65-84 years) and younger adults (age 19-30 years) performed a visually-based, postural tracking task in different body orientations (from 0° to 45°), which necessitated slightly different task goals. On some trials, participants performed a concurrent silent arithmetic task with the visuomotor tracking task. The results demonstrated that sensorimotor control declined with age. Older adults showed greater medial-lateral center of pressure variability compared to younger adults in the precision task. Younger adults displayed a trend to decrease anterior-posterior variability, but older adults exhibited an opposite trend when the body orientation changed from 0° to 45°. The addition of a dual-task situation decreased overall postural variability in both age groups. Age-related changes in postural control may degrade the flexible coordination of the sensory feedback and motor execution. This study suggested that medial-lateral stability may be more sensitive to this age-related decline and may be closely associated with postural instability and falls.

Nominal and functional task difficulty in skill acquisition: Effects on performance in two tests of transfer.

The influence of nominal and functional task difficulty during the acquisition of a motor skill was examined in two tests of transfer of learning. The task involved a ballistic, target-directed, finger action. Nominal task difficulty was defined as the distance of the target from the home position. Functional task difficulty was created by manipulating the progression of target distances during practice. Based on the challenge point framework (Guadagnoli & Lee, 2004), we predicted that practice with a set of targets farther away from the performer would benefit from less functional task difficulty, while practice with a closer set of targets would benefit from more functional task difficulty. In single-task transfer tests, learners who practiced using the high nominal task difficulty targets benefitted in terms of persistence of performance over time. In dual-task transfer tests, groups with an intermediate combined (nominal and functional) task difficulty performed with greater persistence over time on tests of transfer than those who practiced with the highest or lowest combined difficulty. Together these findings suggest that the influences of nominal and functional task difficulty during acquisition are weighted differentially depending upon the transfer test context. The challenge point framework does not accurately capture this complex relationship in its current form.

Nonclassical resident macrophages are important determinants in the development of myocardial fibrosis.

Macrophages are increasingly recognized as a potential therapeutic target in myocardial fibrosis via interactions with fibroblasts. We have characterized macrophage depletion and inhibition of nonclassical macrophage migration, in addition to direct interactions between nonclassical macrophages and fibroblasts in angiotensin II (AngII)-mediated, hypertensive myocardial fibrosis. Macrophage depletion was achieved by daily i.v. clodronate liposomes (-1 day to +3 days) during AngII infusion. Cx3cr1(-/-) mice were used to inhibit nonclassical macrophage migration. Macrophage phenotype (F4/80, CD11b, Ly6C) was characterized by immunofluorescence and flow cytometry. Collagen was assessed by Sirius Red/Fast Green. Quantitative real-time RT-PCR was performed for transcript levels. AngII/wild-type (WT) mice displayed significant infiltrate and fibrosis compared with saline/WT, which was virtually ablated by clodronate liposomes independent of hypertension. In vitro data supported M2 macrophages promoting fibroblast differentiation and collagen production. AngII/Cx3cr1(-/-) mice, however, significantly increased macrophage infiltrate and fibrosis relative to AngII/WT. AngII/Cx3cr1(-/-) mice also showed an M1 phenotypic shift relative to WT mice in, which the predominant phenotype was Ly6C(low), CD206(+) (M2). Myocardial IL-1ß was significantly up-regulated, whereas transforming growth factor ß down-regulated with this M1 shift. We demonstrated that infiltrating macrophages are critical to AngII-mediated myocardial fibrosis by preventing the development of fibrosis after liposomal depletion of circulating monocytes. Our findings also suggest that some macrophages, namely M2, may confer a protective myocardial environment that may prevent excessive tissue injury.

The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a multifactorial pathology limiting the survival of cardiac transplants. The etiology of CAV is unclear, but antibody-mediated and cellular-mediated responses have been implicated. We, and others, have observed ectopic lymphoid structures (ELS) surrounding epicardial coronary arteries with CAV. The potential contribution of these ELS to CAV has not been elucidated. METHODS: Epicardial coronary arteries were collected from 59 transplant patients at 2 centers and studied for ELS presence and composition using immunohistochemistry. The intima and ELS were isolated, and the expression of the genes involved in tertiary lymphoid organ (TLO) formation was measured by quantitative polymerase chain reaction. RESULTS: ELS presence was related to survival after transplantation (p = 0.013) and histologic composition of CAV (p < 0.001). ELS contain B and T lymphocytes, macrophages, and antibody-producing (immunoglobulin [Ig] M and/or IgG) plasma cells. A sub-population of B lymphocytes appeared to be cluster of differentiation (CD)20(+)CD27(+) memory B lymphocytes. The messenger RNA expression of TLO markers (lymphotoxin-ß, and chemokine [C-C motif] ligand 19 and 21) was significantly higher in ELS than in the neointimal lesions. The ELS observed in this study exhibited some TLO markers but did not exhibit the distinct areas rich in B and T lymphocytes that are normally found in classic TLOs. CONCLUSIONS: The cellular composition of the ELS differs from the cellular infiltrate in CAV intimal lesions. The presence of memory B lymphocytes and plasma producing IgM and IgG cells suggests that ELS are related to local antibody production, potentially contributing to antibody-mediated CAV. ELS associated with coronary vessels containing CAV show features of underdeveloped TLOs; classic TLOs may not develop due to patient immunosuppression.

Disruption of collagen homeostasis can reverse established age-related myocardial fibrosis.

Heart failure, the leading cause of hospitalization of elderly patients, is correlated with myocardial fibrosis (ie, deposition of excess extracellular matrix proteins such as collagen). A key regulator of collagen homeostasis is lysyl oxidase (LOX), an enzyme responsible for cross-linking collagen fibers. Our objective was to ameliorate age-related myocardial fibrosis by disrupting collagen cross-linking through inhibition of LOX. The nonreversible LOX inhibitor ß-aminopropionitrile (BAPN) was administered by osmotic minipump to 38-week-old C57BL/6J male mice for 2 weeks. Sirius Red staining of myocardial cross sections revealed a reduction in fibrosis, compared with age-matched controls (5.84 ± 0.30% versus 10.17 ± 1.34%) (P < 0.05), to a level similar to that of young mice at 8 weeks (4.9 ± 1.2%). BAPN significantly reduced COL1A1 mRNA, compared with age-matched mice (3.5 ± 0.3-fold versus 15.2 ± 4.9-fold) (P < 0.05), suggesting that LOX is involved in regulation of collagen synthesis. In accord, fibrotic factor mRNA expression was reduced after BAPN. There was also a novel increase in Ly6C expression by resident macrophages. By interrupting collagen cross-linking by LOX, the BAPN treatment reduced myocardial fibrosis. A novel observation is that BAPN treatment modulated the transforming growth factor-ß pathway, collagen synthesis, and the resident macrophage population. This is especially valuable in terms of potential therapeutic targeting of collagen regulation and thereby age-related myocardial fibrosis.

Varied overground walking training versus body-weight-supported treadmill training in adults within 1 year of stroke: a randomized controlled trial.

BACKGROUND: Although task-related walking training has been recommended after stroke, the theoretical basis, content, and impact of interventions vary across the literature. There is a need for a comparison of different approaches to task-related walking training after stroke. OBJECTIVE: To compare the impact of a motor-learning-science-based overground walking training program with body-weight-supported treadmill training (BWSTT) in ambulatory, community-dwelling adults within 1 year of stroke onset. METHODS: In this rater-blinded, 1:1 parallel, randomized controlled trial, participants were stratified by baseline gait speed. Participants assigned to the Motor Learning Walking Program (MLWP) practiced various overground walking tasks under the supervision of 1 physiotherapist. Cognitive effort was encouraged through random practice and limited provision of feedback and guidance. The BWSTT program emphasized repetition of the normal gait cycle while supported on a treadmill and assisted by 1 to 3 therapy staff. The primary outcome was comfortable gait speed at postintervention assessment (T2). RESULTS: In total, 71 individuals (mean age = 67.3; standard deviation = 11.6 years) with stroke (mean onset = 20.9 [14.1] weeks) were randomized (MLWP, n = 35; BWSTT, n = 36). There was no significant between-group difference in gait speed at T2 (0.002 m/s; 95% confidence interval [CI] = -0.11, 0.12; P > .05). The MLWP group improved by 0.14 m/s (95% CI = 0.09, 0.19), and the BWSTT group improved by 0.14 m/s (95% CI = 0.08, 0.20). CONCLUSIONS: In this sample of community-dwelling adults within 1 year of stroke, a 15-session program of varied overground walking-focused training was not superior to a BWSTT program of equal frequency, duration, and in-session step activity.

The origin, and application of somatosensory evoked potentials as a neurophysiological technique to investigate neuroplasticity.

Somatosensory evoked potentionals (SEPs) can be used to elucidate differences in cortical activity associated with a spinal manipulation (SM) intervention. The purpose of this narrative review is to overview the origin and application of SEPs, a neurophysiological technique to investigate neuroplasticity. Summaries of: 1) parameters for SEP generation and waveform recording; 2) SEP peak nomenclature, interpretation and generators; 3) peaks pertaining to tactile information processing (relevant to both chiropractic and other manual therapies); 4) utilization and application of SEPs; 5) SEPs concurrent with an experimental task and at baseline/control/pretest; 6) SEPs pain studies; and 7) SEPs design (pre/post) and neural reorganization/neuroplasticity; and 8) SEPs and future chiropractic research are all reviewed. Understanding what SEPs are, and their application allows chiropractors, educators, and other manual therapists interested in SM to understand the context, and importance of research findings from SM studies that involve SEPs.

Les potentiels évoqués somesthésiques (PES) peuvent servir à élucider les différences dans l'activité corticale liée à une manipulation vertébrale (MV). La présente revue narrative a pour objet de donner un aperçu de l'origine et de l'application des PES, une technique neurophysiologique servant à étudier la neuroplasticité. Les sujets suivants feront l'objet de résumés : 1) paramètres pour la génération de PES et l'enregistrement des formes d'ondes; 2) nomenclature, interprétation et générateurs du point maximum de PES; 3) points maximums relatifs au traitement de l'information tactile (pertinent pour la chiropratique et les autres thérapies manuelles); 4) l'utilisation et l'application des PES; 5) PES en même temps qu'une tâche expérimentale et au point de référence/prétest; 6) les PES et les études sur la douleur; 7) conception des PES (pré/post) et réorganisation neuronale/neuroplasticité; 8) les PES et la recherche future en chiropratique. Comprendre ce que sont les PES ainsi que leur application permet aux chiropraticiens, aux éducateurs et aux autres thérapeutes manuels qui s'intéressent à la MV de comprendre le contexte et l'importance des conclusions des recherches sur la MV où l'on a recours aux PES.

The impact and specificity of nerve perturbation on novel vibrotactile sensory letter learning.

The purposes of this study were to determine if induced radiating paresthesia interferes with (a) acquisition and/or (b) utilization of complex tactile information, and (c) identify whether interference reflects tactile masking or response competition. Radiating ulnar (experiment 1) and median (experiment 2) nerve paresthesia was quantified on ulnar innervated vibrotactile Morse code letter acquisition and recollection tasks. Induced paresthesia differentially impacted letter acquisition and recollection, but only when presented to the same anatomical spatial location.

What roles do errors serve in motor skill learning? An examination of two theoretical predictions.

Easy-to-difficult and difficult-to-easy progressions of task difficulty during skill acquisition were examined in 2 experiments that assessed retention, dual-task, and transfer tests of learning. Findings of the first experiment suggest that an easy-to difficult progression did not consistently induce implicit learning processes and was not consistently beneficial to performance under a secondary-task load. The findings of experiment two did not support the predictions made based on schema theory and only partially supported predictions based on reinvestment theory. The authors interpret these findings to suggest that the timing of error in relation to the difficulty of the task (functional task difficulty) plays a role in the transfer of learning to novel versions of a task.

Impact of donor benign intimal thickening on cardiac allograft vasculopathy.

BACKGROUND: Epicardial cardiac allograft vasculopathy (CAV) is commonly described as a homogeneous smooth muscle cell (SMC)-rich inward intimal lesion with the SMC oriented circumferentially around the vessel. Recent findings have called this description into question. In this study we aimed to clarify the clinical presentation of epicardial CAV. METHODS: Autopsied samples of the 3 major coronaries were analyzed from patients fitting cardiac donor criteria (n = 10) and patients who had undergone cardiac transplantation (n = 34). Histology and immunohistochemistry were performed to identify cellular components of CAV, and image analysis was used to measure the various vascular compartments. RESULTS: Of the 34 cases examined, 28 of the epicardial intimal lesions contained 2 clearly definable layers overlying the media. The layer most adjacent to the media was SMC-rich, with the SMC oriented longitudinally along the vessel length and containing few macrophages, both characteristics of donor-derived benign intimal thickening (BIT). Transplants harvested at 1, 4 or 10 days post-transplant confirmed retention of BIT after transplantation. Image analysis of later transplants supported a hypothesis of carry-over BIT in CAV. The more lumenal CAV layer more closely resembled naturally occurring atherosclerosis. CONCLUSIONS: We propose that retention of the SMC-rich BIT layer after transplantation accounts, to a large extent, for the donor-derived, SMC-rich nature of human CAV, and that perturbation of the BIT provides the inflammatory foundation for the development of an accelerated atherosclerosis in the epicardial coronaries of transplant patients. This expanding accelerated atherosclerosis along with the underlying BIT demonstrates the characteristics ascribed to CAV.

The gunslinger effect: why are movements made faster when responding to versus initiating an action?

The authors replicated and extended results from the gunfight paradigm (A. Welchman, J. Stanley, M. Schomers, R. Miall, & H. Bulthoff, 2010a) in which participants moved faster when reacting to the perceived initiation of an opponent compared to initiating an action themselves. In addition to replicating these movement time effects, the authors found that time to peak velocity, peak velocity, and movement-endpoint dispersions were similarly impacted. The findings are discussed in terms of a triggering mechanism involved in ballistic and internally generated movements.

Regulation and role of connective tissue growth factor in AngII-induced myocardial fibrosis.

Exposure of rodents to angiotensin II (AngII) is a common model of fibrosis. We have previously shown that cellular infiltration of bone marrow-derived progenitor cells (fibrocytes) occurs before deposition of extracellular matrix and is associated with the production of connective tissue growth factor (CTGF). In the present study, we characterized the role of CTGF in promoting fibrocyte accumulation and regulation after AngII exposure. In animals exposed to AngII using osmotic minipumps (2.0 µg/kg per min), myocardial CTGF mRNA peaked at 6 hours (21-fold; P < 0.01), whereas transforming growth factor-ß (TGF-ß) peaked at 3 days (fivefold; P < 0.05) compared with saline control. Early CTGF expression occurred before fibrocyte migration (1 day) into the myocardium or ECM deposition (3 days). CTGF protein expression was evident by day 3 of AngII exposure and seemed to be localized to resident cells. Isolated cardiomyocytes and microvascular endothelial cells responded to AngII with increased CTGF production (2.1-fold and 2.8-fold, respectively; P < 0.05), which was abolished with the addition of anti-TGF-ß neutralizing antibody. The effect of CTGF on isolated fibrocytes suggested a role in fibrocyte proliferation (twofold; P < 0.05) and collagen production (2.3-fold; P < 0.05). In summary, we provide strong evidence that AngII exposure first resulted in Smad2-dependent production of CTGF by resident cells (6 hours), well before the accumulation of fibrocytes or TGF-ß mRNA up-regulation. In addition, CTGF contributes to fibrocyte proliferation in the myocardium and enhances fibrocyte differentiation into a myofibroblast phenotype responsible for ECM deposition.

Treatment with activated protein C (aPC) is protective during the development of myocardial fibrosis: an angiotensin II infusion model in mice.

AIMS: Myocardial fibrosis contributes to the development of heart failure. Activated Protein C (aPC) is a circulating anticoagulant with anti-inflammatory and cytoprotective properties. Using a model of myocardial fibrosis second to Angiotensin II (AngII) infusion, we investigated the novel therapeutic function aPC in the development of fibrosis. METHODS AND RESULTS: C57Bl/6 and Tie2-EPCR mice were infused with AngII (2.0 µg/kg/min), AngII and aPC (0.4 µg/kg/min) or saline for 3d. Hearts were harvested and processed for analysis or used for cellular isolation. Basic histology and collagen deposition were assessed using histologic stains. Transcript levels of molecular mediators were analyzed by quantitative RT-PCR. Mice infused with AngII exhibited multifocal areas of myocardial cellular infiltration associated with significant collagen deposition compared to saline control animals (p<0.01). AngII-aPC infusion inhibited this cellular infiltration and the corresponding collagen deposition. AngII-aPC infusion also inhibited significant expression of the pro-fibrotic cytokines TGF-ß1, CTGF and PDGF found in AngII only infused animals (p<0.05). aPC signals through its receptor, EPCR. Using Tie2-EPCR animals, where endothelial cells over-express EPCR and exhibit enhanced aPC-EPCR signaling, no significant reduction in cellular infiltration or fibrosis was evident with AngII infusion suggesting aPC-mediate protection is endothelial cell independent. Isolated infiltrating cells expressed significant EPCR transcripts suggesting a direct effect on infiltrating cells. CONCLUSIONS: This data indicates that aPC treatment abrogates the fibrogenic response to AngII. aPC does not appear to confer protection by stimulating the endothelium but by acting directly on the infiltrating cells, potentially inhibiting migration or activation.

Multijoint error compensation mediates unstable object control.

A key feature of skilled object control is the ability to correct performance errors. This process is not straightforward for unstable objects (e.g., inverted pendulum or "stick" balancing) because the mechanics of the object are sensitive to small control errors, which can lead to rapid performance changes. In this study, we have characterized joint recruitment and coordination processes in an unstable object control task. Our objective was to determine whether skill acquisition involves changes in the recruitment of individual joints or distributed error compensation. To address this problem, we monitored stick-balancing performance across four experimental sessions. We confirmed that subjects learned the task by showing an increase in the stability and length of balancing trials across training sessions. We demonstrated that motor learning led to the development of a multijoint error compensation strategy such that after training, subjects preferentially constrained joint angle variance that jeopardized task performance. The selective constraint of destabilizing joint angle variance was an important metric of motor learning. Finally, we performed a combined uncontrolled manifold-permutation analysis to ensure the variance structure was not confounded by differences in the variance of individual joint angles. We showed that reliance on multijoint error compensation increased, whereas individual joint variation (primarily at the wrist joint) decreased systematically with training. We propose a learning mechanism that is based on the accurate estimation of sensory states.

Cyclosporine immunosuppression does not prevent the production of donor-specific antibody capable of mediating allograft vasculopathy.

BACKGROUND: Late cardiac graft rejection, primarily mediated by allograft vasculopathy (AV), remains a major limitation to cardiac transplantation, even in the face of significant calcineurin inhibitor (CNI) immunosuppression. The role played by alloantibody in AV is unclear. Evidence that CNI immunosuppression suppresses CD4(+) T-cell function would suggest that antibody production and effector function would be severely limited in CNI-treated patients. In this study we examine the capacity of CNI-treated animals to develop effective alloantibody that can mediate AV. METHODS: Wild-type (WT) B6 mice were alloimmunized using donor splenocytes or a fully major histocompatibility complex-mismatched allogeneic abdominal aortic graft in the presence of CNI immunosuppression (30 or 50 mg/kg/day cyclosporine A). Anti-serum was harvested and tested using complement-dependent in vitro cytotoxicity assays. Anti-serum was passively transferred to immunodeficient RAG1(-/-) recipients of allogeneic grafts. C4d deposition was quantified in the allografts from WT recipients. RESULTS: CNI immunosuppression did not prevent the development of alloantibody in response to either immunization method (p < 0.05). Passive transfer of anti-serum generated AV lesions in immunodeficient graft recipients and mediated complement-dependent destruction of donor cells (p < 0.05). C4d deposition was localized to the media of grafts of CNI treated animals. CONCLUSIONS: CNI therapy does not prevent the production of alloantibody with the capacity to mediate AV. C4d deposition in the media suggests a role for medial smooth muscle cell loss in antibody-mediated AV lesion development in our model.

Fibroblast progenitor cells are recruited into the myocardium prior to the development of myocardial fibrosis.

Using an established model of myocardial hypertrophy and fibrosis after angiotensin II (AngII) infusion, our aim was to characterize the early cellular element involved in the development of myocardial fibrosis in detail. Male Lewis rats were infused with saline or AngII (0.7 mg/kg per day) for up to seven days. Collagen deposition and cellular infiltration were identified by histology stains. Infiltrating cells were grown in vitro and examined by flow cytometry and immunostaining. Chemokine expression was measured using qRT-PCR. AngII infusion resulted in multifocal myocardial cellular infiltration (peak at three days) that preceded collagen deposition. Monocyte chemotactic protein (MCP)-1 transcripts peaked after one day of AngII exposure. Using a triple-labelling technique, the infiltrating cells were found to express markers of leucocyte (ED1(+)), mesenchymal [α-smooth muscle actin (SMA)(+)] and haematopeotic progenitor cells (CD133(+)) suggesting a fibroblast progenitor phenotype. In vitro, ED1(+)/SMA(+)/CD133(+) cells were isolated and grown from AngII-exposed animals. Comparatively few cells were cultured from untreated control hearts, and they were found to be ED1(-)/SMA(+)/CD133(-). We provide evidence that myocardial ECM deposition is preceded by infiltration into the myocardium by cells that express a combination of haematopoietic (ED1, CD133) and mesenchymal (SMA) cell markers, which is a characteristic of the phenotype of fibroblast precursor cells, termed fibrocytes. This suggests that fibrocytes rather than (as is often presumed) leucocytes may have effector functions in the initiation of myocardial fibrosis.